Systems and methods for providing zones of selective thermal therapy

ABSTRACT

The present disclosure describes for at least two zones of selective thermal therapy of the body. Three-port extracorporeal circuits are described that can be used to establish at least two zones of selective thermal therapy of the body. The example three-port extracorporeal circuit includes a branching section that provides for setting the temperature of blood injected into two different portions of the body at differing temperature levels, to provide. at least two zones of selective thermal therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.14/932,414, filed Nov. 4, 2015, and entitled “Systems and Methods forProviding Zones of Selective Thermal Therapy,” the entire contents ofwhich are incorporated herein by reference in their entirety.

BACKGROUND

Hypothermia, i.e., a controlled lowering of the temperature of portionsof the body, can be used to provide some therapeutic advantages. Thus,it may be intentionally induced as therapeutic hypothermia in certainprocedures. For example, in the medical community, hypothermia isconsidered as an accepted neuroprotectant during cardiovascular surgery.Hypothermia is also sometimes induced as a neuroprotectant duringneurosurgery. Therapeutic hypothermia can be used beneficially toprevent or reduce the effect of tissue damage from ischemic injuries andother injuries. For example, tissue damage that follows ischemicinjuries can begin at the onset of ischemia and continue throughout thereperfusion phase after blood flow is restored. Both preclinical andclinical studies support the observation that the reperfusion phase canlast from hours to days, and that therapeutic hypothermia can be usedbeneficially to block much of the injury in that phase.

SUMMARY

This instant disclosure provides example systems, devices, apparatus andmethods that provide at least two zones of selective thermal therapy ofthe body using a three-port extracorporeal circuit. The examplethree-port extracorporeal circuit includes a branching section thatprovides for setting the temperature of blood injected into twodifferent portions of the body at differing temperature levels, therebyproviding at least two zones of selective thermal therapy.

An example extracorporeal circuit can include an injector memberincluding a distal tip disposed at a vascular location, a first port towithdraw blood from the body, a second port to return blood to the body,a first pump disposed between the first port and the second port to pumpblood from the first port to the second port, a branching sectionpositioned between the first pump and second port, and a third portcoupled to the branching section. The third port is positioned on anextracorporeal side of the injector member, and the second pumppositioned between the branching section and the third port.

The example system can also include a first heat exchanger disposedbetween the first port and the second port, and a second heat exchangerdisposed between the second pump and the injector member. The first heatexchanger can be configured to set a temperature of blood injected intothe second port to a first temperature level. The second heat exchangercan be configured to set the temperature of blood injected into theinjector member to a second temperature level different from the firsttemperature level. The first heat exchanger can be disposed between thebranching section and the first port or between the branching sectionand the second port.

An example system for providing at least two zones of selective thermaltherapy can include an occlusion component, or an imposed minimumconductance component, disposed proximate to the distal tip of theinjector member.

An example system for providing at least two zones of selective thermaltherapy can include a controlled flow partitioning system proximal tothe distal tip, to be used to compute a value for a conductance of aportion of the vasculature external to an injector member.

An example controlled flow partitioning system can include a firstpressure sensor for measuring a first pressure proximate to a distal tipof the at least one injector member, and a second pressure sensor formeasuring a second pressure, the second pressure sensor being disposedproximal from the distal tip. The second pump serves as an injectionflow rate source to cause injection flow at a predetermined flow ratepattern at the injector member.

Example systems, devices, and apparatus are described for providingsupport that include a systemic perfusion extracorporeal circuit (SPEC),a local perfusion extracorporeal circuit (LPEC) for perfusing a localtarget region of a body, and a console. The SPEC includes a SPEC inputflow port, a SPEC output flow port, and a SPEC pump. The SPEC input flowport and SPEC output flow port are in contact with blood flowing withinthe vasculature at a peripheral portion of the body. The LPEC includes aLPEC input flow port, a LPEC output flow port, a LPEC pump, and a LPECheat exchanger. The LPEC input flow port and LPEC output flow port arein contact with blood flowing within the vasculature to the local targetregion of the body. The LPEC heat exchanger controls the temperature ofthe blood returned to the local target region of the body for the localperfusion. A controlled flow partitioning system is disposed proximateto a distal tip of the LPEC injector member. The controlled flowpartitioning system includes a first pressure sensor for measuring afirst pressure proximate to the distal tip of the LPEC injector member,and a second pressure sensor for measuring a second pressure. The secondpressure sensor is disposed proximal from the distal tip of the LPECinjector member. The second pump serves as an injection flow rate sourceto cause injection flow at a predetermined flow rate pattern at theinjector member. One or more SPEC temperature sensors are coupled to thebody, to indicate average core body temperature and/or average systemtemperature of the body perfused by the SPEC. One or more LPECtemperature sensors are coupled to the local target region of the bodyto indicate temperature within the target region. The console includesat least one processing unit that is programmed to receive dataindicative of measurements of the first pressure and the second pressureover a time interval T with the flow of blood injected at the distal tipat the predetermined flow rate pattern, and compute the conductance asat least one of a proximal exterior conductance or a distal exteriorconductance at the distal tip of the LPEC injector member, using thedata indicative of the measurements of the first pressure and the secondpressure and the predetermined flow rate pattern.

Example systems, devices, and apparatus can be configured to implement amethod for establishing and controlling two different temperature zonesof at least portions of a body for at least portions of a treatmentprocedure for a patient that suffered a local or global ischemic insultor circulation damage. The example method includes coupling a systemicperfusion extracorporeal circuit (SPEC) to the body using a peripheralplaced loop and coupling a local perfusion extracorporeal circuit (LPEC)to blood flowing within the vasculature to a local target region of thebody. The SPEC includes a SPEC input flow port and a SPEC output flowport to be in contact with blood flowing within the vasculature, a SPECpump, and a SPEC heat exchanger. The LPEC includes a LPEC injectormember comprising a distal tip, to be in contact with blood flowingwithin the vasculature, a LPEC pump, and a LPEC heat exchanger. The LPECinjector member is disposed to perfuse the local target region of thebody. At least one of an imposed minimum conductance component, or acontrolled flow partitioning system is disposed proximate to the distaltip of the LPEC injector member. The method further includes positioningat least one SPEC sensor to measure the average core body temperatureand/or average system temperature of the body perfused by the SPEC,positioning at least one LPEC sensor to measure the temperature of thelocal target region perfused by the LPEC, performing operational stepsof at least a minimum operating sequence, and implementing a controlprocedure to record measurements of the at least one LPEC sensor and atleast one SPEC sensor and to control independently a rate of blood flowand a heat exchanger temperature of the SPEC and LPEC, respectively. Thecontrol procedure causes the SPEC to control the temperature of theblood injected by the SPEC to adjust the temperature measurementreported by the SPEC temperature sensors to stay within a target corebody temperature range, and causes the LPEC to control the temperatureof the blood injected to the target region such that the one or moreLPEC temperature sensors report a temperature measurement according to aspecified pattern of target region temperature values.

Example systems, devices, and apparatus are described for providingselective thermal therapy. An example system can include a firstelongated element with a first wall defining a first lumen having afirst lumen distal end and a first lumen proximal end and a length fromthe proximal end to the distal end, where the first lumen is a deliverylumen for delivering thermally treated blood to a target site in thebody, an exit port located on the first lumen, the exit port fordelivering the thermally treated blood to the target site, at least oneof an imposed minimum conductance component or a controlled flowpartitioning system positioned on the first lumen, proximal to the exitport, and a second elongated element with a second wall. A second lumenis defined as a space between the first wall and the second wall, andthe second lumen is coaxial to the first lumen, the second lumen havinga second lumen proximal end and a second lumen distal end. The secondlumen is a supply lumen for receiving normothermic blood from the body,the second lumen distal end positioned relative to the first lumendistal end such that the second lumen distal end is in such proximity tothe first lumen distal end so that the second lumen acts as aninsulating layer along a majority of the length of the first lumen whenreceiving the normothermic blood. The second elongated element isinsertable into an artery of the body at a peripheral location of thebody and adapted to extend to a remote location of the body. The examplesystem includes an inlet positioned on the second elongated element, theinlet proximal to at least one of the imposed minimum conductancecomponent or the controlled flow partitioning system, the inlet forreceiving the normothermic blood. The example system further includes acontrol unit in fluid communication with the proximal ends of the firstlumen and the second lumen, the control unit including: a supply bloodinlet in fluid communication with the second lumen, the supply bloodinlet for receiving the normothermic blood from the body, a thermaladjustor in fluid communication with the supply blood inlet, the thermaladjustor configured for changing a temperature of the receivednormothermic blood so as to provide the thermally treated blood, and adelivery blood outlet in fluid communication with the thermal adjustorand in fluid communication with the first lumen, the delivery bloodoutlet for providing the thermally treated blood to the first lumen.

Example systems, devices, and apparatus are described for providingselective thermal therapy. An example device can include a firstelongated element with a first wall, a delivery lumen defined by a spacewithin the first wall, a second elongated element with a second wall, asupply lumen defined by a space between the first wall and the secondwall, and a control unit in fluid communication with the supply lumenand the delivery lumen. The control unit includes a supply blood inletin fluid communication with the supply lumen, the supply blood inlet forreceiving normothermic blood from the body, and a delivery blood outletin fluid communication in fluid communication with said delivery lumen,said delivery blood outlet for providing thermally the thermally treatedblood to said delivery lumen. The supply lumen delivers normothermalblood to the control unit located outside of the body. The deliverylumen receives thermally treated blood from the control unit andsupplies the thermally treated blood to a target site in the body, wherethe supply lumen is coaxial to said delivery lumen, where said supplylumen is positioned around a majority of said delivery lumen so thatsaid supply lumen acts as the insulating layer along a majority of saiddelivery lumen when receiving the thermally treated blood, and wheresaid supply lumen, the control unit and said delivery lumen form aclosed system. The second elongated element is insertable into an arteryof the body at a peripheral location of the body and adapted to extendto a remote location of the body. At least one of an imposed minimumconductance component or a controlled flow partitioning system ispositioned on said delivery lumen in a location which is proximal to adistal end of said delivery lumen and distal to a distal end of saidsupply lumen.

It should be appreciated that all combinations of the foregoing conceptsand additional concepts discussed in greater detail below (provided suchconcepts are not mutually inconsistent) are contemplated as being partof the inventive subject matter disclosed herein. In particular, allcombinations of claimed subject matter appearing at the end of thisdisclosure are contemplated as being part of the inventive subjectmatter disclosed herein. It should also be appreciated that terminologyexplicitly employed herein that also may appear in any disclosureincorporated by reference should be accorded a meaning most consistentwith the particular concepts disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

One of ordinary skill in the art will understand that the drawingsprimarily are for illustrative purposes and are not intended to limitthe scope of the inventive subject matter described herein. The drawingsare not necessarily to scale; in some instances, various aspects of theinventive subject matter disclosed herein may be shown exaggerated orenlarged in the drawings to facilitate an understanding of differentfeatures. In the drawings, like reference characters generally refer tolike features (e.g., functionally similar and/or structurally similarelements).

FIG. 1A shows a schematic of an example catheter system, according toprinciples of the present disclosure.

FIGS. 1B-1C show example plots of the fluid conductance in the vascularspace across the boundary.

FIG. 2A shows an example extracorporeal circuit, according to principlesof the present disclosure.

FIGS. 2B-2C show schematics of another catheter system, according toprinciples of the present disclosure.

FIGS. 3A-3B show examples of another catheter system, according toprinciples of the present disclosure.

FIGS. 4A-4B show examples of another catheter system, according toprinciples of the present disclosure.

FIG. 4C shows an example of another catheter system, according toprinciples of the present disclosure.

FIGS. 4D(i) and 4D(ii) an example of another catheter system, accordingto principles of the present disclosure.

FIGS. 5A(i) and 5A(ii) show an example of a biased valve on an aperturein an example catheter system, according to principles of the presentdisclosure.

FIG. 5B shows an example of a biased valve on an aperture in an examplecatheter system, according to principles of the present disclosure.

FIG. 5C shows an example of a biased valve on an aperture in an examplecatheter system, according to principles of the present disclosure.

FIG. 6A shows an example injector member coupled to pressure sensors inan example catheter system, according to principles of the presentdisclosure.

FIG. 6B shows another example injector member coupled to pressuresensors in an example catheter system, according to principles of thepresent disclosure.

FIG. 6C shows an example catheter coupled to pressure sensors, accordingto principles of the present disclosure.

FIG. 6D shows another example catheter coupled to pressure sensors,according to principles of the present disclosure.

FIG. 7A shows an example extracorporeal circuit system, according toprinciples of the present disclosure.

FIG. 7B shows another extracorporeal circuit system, according toprinciples of the present disclosure.

FIG. 7C shows another extracorporeal circuit system, according toprinciples of the present disclosure.

FIG. 8A shows an example extracorporeal circuit system coupled to aconsole, according to principles of the present disclosure.

FIG. 8B shows another example extracorporeal circuit system coupled to aconsole, according to principles of the present disclosure.

FIG. 9 is a block diagram showing an example computing device, accordingto principles of the present disclosure.

FIGS. 10A-10B show flow diagrams illustrating example methods, accordingto principles of the present disclosure.

FIG. 11 is an example computational device block diagram, according toprinciples of the present disclosure.

DETAILED DESCRIPTION

Following below are more detailed descriptions of various conceptsrelated to, and embodiments of, systems, devices, apparatus and methodsthat allow for control of at least two zones of selective thermaltherapy. It should be appreciated that various concepts introduced aboveand discussed in greater detail below may be implemented in any ofnumerous ways, as the disclosed concepts are not limited to anyparticular manner of implementation. Examples of specificimplementations and applications are provided primarily for illustrativepurposes.

As used herein, the term “includes” means includes but is not limitedto, the term “including” means including but not limited to. The term“based on” means based at least in part on.

With respect to surfaces described herein in connection with variousexamples of the principles herein, any references to “top” surface and“bottom” surface are used primarily to indicate relative position,alignment and/or orientation of various elements/components with respectto the substrate and each other, and these terms do not necessarilyindicate any particular frame of reference (e.g., a gravitational frameof reference). Thus, reference to a “bottom” of a surface or layer doesnot necessarily require that the indicated surface or layer be facing aground surface. Similarly, terms such as “over,” “under,” “above,”“beneath” and the like do not necessarily indicate any particular frameof reference, such as a gravitational frame of reference, but rather areused primarily to indicate relative position, alignment and/ororientation of various elements/components with respect to the surface,and each other.

The terms “disposed on” and “disposed over” encompass the meaning of“embedded in,” including “partially embedded in.” In addition, referenceto feature A being “disposed on,” “disposed between,” or “disposed over”feature B encompasses examples where feature A is in contact withfeature B, as well as examples where other layers and/or othercomponents are positioned between feature A and feature B.

As used herein, the term “proximal” refers to a direction towards aportion of a catheter, an injector member, or other instrument that auser would operate, such as but not limited to a grip or other handle.As used herein, the term “distal” refers to a direction away from thegrip or other handle of the catheter, injector member, or otherinstrument. For example the tip of the injector member is disposed at adistal portion of the injector member.

Example systems, devices, apparatus and methods are described forcontrol of at least two zones of selective thermal therapy, that allowcontrolled lowering of the temperature of portions of the body. Theexample systems, devices, apparatus and methods can be used tointentionally induce therapeutic hypothermia in certain operative orother medical procedures, such as but not limited to cardiovascularsurgery or neurosurgery. For example, systems, devices, apparatus andmethods described herein can used to prevent or reduce tissue damagethat can follow ischemic injuries, which would normally begin at theonset of ischemia and continue throughout the reperfusion phase afterblood flow is restored. Both preclinical and clinical studies supportthe observation that the reperfusion phase can last from hours to days.The therapeutic hypothermia that can be achieved using the examplesystems, devices, apparatus and methods described herein can be usedbeneficially to block much of the injury or other type of tissue damagein that phase.

Example systems, devices, apparatus and methods are described thatprovide at least two zones of selective thermal therapy of the bodyusing a three-port extracorporeal circuit. An example three-portextracorporeal circuit according to the principles herein can include abranching section that provides for setting the temperature of bloodinjected into two different portions of the body at differingtemperature levels, thereby providing at least two zones of selectivethermal therapy.

An example extracorporeal circuit can include an injector memberincluding a distal tip disposed at a vascular location, a first port towithdraw blood from the body, a second port to return blood to the body,a first pump disposed between the first port and the second port to pumpblood from the first port to the second port, a branching sectionpositioned between the first pump and second port, and a third portcoupled to the branching section. The third port is positioned on anextracorporeal side of the injector member, and the second pumppositioned between the branching section and the third port.

In addition, during certain procedures using a catheter, blood flow avein or an artery may be occluded. Whenever blood flow is at leastpartially blocked, no-flow or low-flow regions, including dead-zones,can arise in portions of the vasculature. For example, intravascularcatheters or other similar devices can include occlusion devices forcontrolling or blocking flow in an artery or vein. Under certaincircumstances, occluding the flow of blood in an artery or vein cancreate zones of significantly diminished blood flow, or no-flow region,where the blood is substantially stagnant. These zones are referred toherein as “dead zones” or “no-flow zones” Tissue may become starved ofblood flow, and possibly be compromised, if the no-flow or low-flowregion (including dead-zone) persists for lengthy periods of time. Insome cases, the prolonged creation of a dead zone in blood flow mayenhance the risk of creating a thrombus or blood clot, which isassociated with increased risk of an embolism in a patient. The questionof arises as to how to minimize these risks from the blockage.

In some systems, the risk of cutoff of blood flow to the tissue fed byan artery is addressed by adding bypass or perfusion lumens, such asdescribed in U.S. Pat. Nos. 5,046,503 and 5,176,638.

The present disclosure also describes various example systems, methods,and apparatus for controlling the flow of blood in a portion of anartery or vein, to control the occurrence and duration in time oflow-flow or no-flow regions in a portion of the vasculature. As anon-limiting example, the systems, devices, apparatus and methods can beused to control the occurrence and time duration in time of dead-zoneregions in a portion of the vasculature

In some examples, systems, methods, and apparatus are described forcontrolling (including reducing) flow stagnation during use ofintravascular catheters or other similar devices. Example systems,apparatus, and methods are described for controlling or reducing theoccurrence of no-flow or low-flow zones in the vasculature based on dataindicative of the conductance of regions of the vasculature. The controlof flow stagnation can be achieved using at least one imposed minimumconductance component or using a controlled flow partitioning system. Anexample imposed minimum conductance component can be used to impose adesired, known value of conductance in regions of the vasculature. Ifthe conductance outside the injector member is known, the fluidinjection level at the injection member can be controlled such thatthere is an amount of fluid flow to flush in an area that would normallyform a no-flow or low-flow zone (including a dead zone). An examplecontrolled flow partitioning system can use sensor measurements tocompute the conductance in a region of the vasculature, therebyproviding a known value of conductance. That is, either of these systemsof methodologies can be used to provide a known value of conductanceexterior to the catheter member. With these known values of conductance,the fluid flow can be controlled to ensure that either no no-flow orlow-flow zones occur in the vasculature, or the duration of time ofoccurrence of the no no-flow or low-flow zones does not result in damageto tissue or other damage.

Reducing the occurrence of flow stagnation reduces or eliminates thepossibility of dead zones or no-flow zones forming in portions of thevasculature.

According to some example implementations, the flow stagnation controlcan be achieved through use of a controlled flow partitioning system.The controlled flow partitioning system includes components formeasuring both the proximal exterior conductance and the distal exteriorconductance. The measurements to prevent dead-flow zones in the regionproximal to an injector member by modifying the flow injected at theinjection member. The example devices, systems, and methods can beoperated passively to measure fluid flow, or can be used actively tomeasure fluid flow through introduction or withdrawal of an amount offluid.

The present disclosure also describes devices, systems, and methods thatcan be operated actively to prevent or reduce the occurrence of(including to flush) a dead zone that can form in a portion of thevasculature proximate to the catheter during operation.

The term “imposed minimum conductance component” is used herein to referto a component that controls the reduction of the flow rate in avasculature segment, while ensuring that the flow rate does not go belowa certain minimum value based on an imposed minimum conductance level.Conductance herein is the inverse of resistance. In various examples,the minimum conductance level can be used to control the flow to a fixedvalue of flow rate (referred to herein as a “fixed-constant”), or as anaveraged value of flow rate over a time cycle t that is small ascompared to the length of time T of a procedure, i.e., where t<<T(referred to herein as a “fixed-average”). For example, the time cycle tcan be on the order of a heartbeat or minutes, while time period T canbe the time of an operation or other procedure, lasting one or morehours.

According to some example embodiments, the flow stagnation control canbe achieved through use of the imposed minimum conductance componentsand systems that are configured to allow improved flow control inextracorporeal blood return. The present disclosure also providesvarious example imposed minimum conductance components that limit orprevent the formation of dead zones in a region of the artery or veinproximate to the imposed minimum conductance components, and alsoprovides specific dead zone flushing devices or sub-systems.

As used herein, an “injector member” is a device or component thatincludes a lumen. In an example, the lumen can be used for injectingfluid into the vasculature, either as part of an independent cathetersystem, or as a component of an example extracorporeal circuit systemthat is used to inject blood into the vasculature at a specific locationin the body.

As used herein, the term “vasculature injection point” refers to themost distal location in the vasculature, away from a catheter entry orvascular puncture location, at which blood is injected into the body.

As used herein, the term “peripheral placed loop” refers to an exampleextracorporeal circuit that has blood output (from body to circuit) andblood input (from circuit to body) catheters (or other an input flowport and/or output flow port member) that can be placed in contact witha portion of the vasculature of the body, without detailed guidance fromfluoroscopy or any other equivalent systems that is normally used tosteer devices past arterial or venous branches. This is a subset of allpossible placements, some through the peripheral circulation and somethrough the central circulation.

The term “peripheral” is used herein differently than used in referringto a peripheral circulation system. For example, the catheters (or otheran input flow port and/or output flow port member) may be placed incontact with the vena cava, or low into the descending aorta or iliacartery, without using fluoroscopy. These are sometimes considered partof the central system, rather than the peripheral circulation system.

As used herein, the term “systemic perfusion system” refers to a systemthat couples to blood in the heart via an injector member coupleddirectly to the main venous feeds to the heart, such as the vena cava(inferior vena cava or superior vena cava), or iliac vein.

As used herein, the term “local perfusion system” refers to a systemthat has an injector member placed such that a dominant fraction (morethan about 50%) of the blood injected feeds to an organ system beforereturning through the general circulation to the heart.

As used herein, the term “proximal exterior conductance” means theconductance in the space exterior to the device, i.e. between the deviceand the vascular wall, along a region proximal to the injection membertip.

As used herein, the term “distal exterior conductance” means the totalconductance from the site of injection at the tip of an injection memberinto the distal vasculature. For injection members on the arterial sideof the vasculature, this is the conductance from the tip to the venousside of the circulation.

As used herein, the term “controlled flow partitioning system” is asystem for measuring or computing values for either or both the proximalexterior conductance and the distal exterior conductance, which thenuses those measurements to prevent dead-flow zones in the regionproximal to an injector member by modifying the flow rate injected atthe injection member. Such a system, as used herein is composed of atleast two pressure sensors and a displacement or flow rate controllingpump on the extracorporeal circuit side of the injector member directlycontrolling flow rate through the injector member. In any exampleherein, the controlled flow partitioning system can include adistributed array of pressure sensors.

As used herein, the term “flow rate pattern” refers to a functional formof flow rates over a set period of time. For example, the flow of fluidcan be set at a fluid flow rate source such that the fluid flow followsthe values set by the flow rate pattern. In various examples, the flowrate pattern can be a specified functional form, such as but not limitedto a sinusoidal functional form, a sawtooth functional form, astep-function functional form, or another periodic functional form inthe art (including more complex functional forms). In other examples,where the flow rate pattern has an irregular functional form, the valueof flow rate can be measured at regular time intervals over a specifiedperiod of time to provide an approximation of the irregular functionalform.

In non-limiting example herein, an imposed minimum conductance componentcan be configured to set a known, specified proximal conductance arounda distal region of an injection member. That proximal conductance canprevent the formation of any no-flow or dead-flow zones. As anotherexample, in a controlled flow partitioning system according to theprinciples herein, the conductance that is present in the proximalexterior of an injection member is measured (instead of that conductancebeing created) and that measurement is used to control the flow rate andflushing of relevant zones (including any no-flow or dead-flow zones).

In an example herein, a “biased valve” refers to a component in the wallof a catheter segment between an internal lumen and the outside of theshaft which is exposed to the vasculature. In an example, the “biasedvalue” can be configured such that, if the pressure inside the lumen islarger than the pressure outside the shaft, there is a value ofconductance G_(forward) established across the valve. In anotherexample, the “biased valve” can be configured such that, if the pressureinside the lumen is smaller than the pressure outside the shaft, thereis a value conductance G_(backward) established across the valve. In anexample, the reasonable pressure differences between the lumen and thevasculature can be expressed as G_(forward)>>G_(backward), orG_(backward) is very small or near zero.

FIG. 1A shows a schematic of an example catheter system 100 thatincludes a shaft 101 of a device that is disposed in a portion of thevasculature. FIG. 1A also shows a plane 102 through an occlusioncomponent 103 that is mounted on the shaft 101 and is part of thedevice. The shaft holding device 101 may include a lumen that passesthrough the device. In an example catheter system 100, the occlusioncomponent 103 may include a balloon that is inflated using saline orother solution. Another example occlusion component 103 may include amembrane that is expanded to press against the arterial wall using theforce exerted by a spring or other mechanical actuation. In an example,the occlusion component 103 can be configured to extend from the shaftdevice 101 of the catheter system 100 to touch and seal against thewalls of the artery or vein, to significantly reduce or prevent flow. Asshown in FIG. 1A, the example plane 102 is perpendicular to the vascularsection. The example occlusion component 103 is used according to theprinciples herein to modify the fluid flow across plane 102. The fluidflow relates to the flow outside of the base holding shaft. The degreeof flow is driven by a difference in pressure between the region beforethe occlusion component 103 (Pb) and the region after (Pa).

FIGS. 1B and 1C show example graphs of the fluid conductance (G₀) versustime in the vascular space across the plane 102 through the occlusioncomponent 103. FIG. 1B shows the fluid conductance (G₀) versus time fora full occlusion achieved using occlusion component 103. In the exampleof FIG. 1B, the fluidic conductance is reduced during the time period Δtwhen the occlusion component is activated to fully occlude the vascularspace. The plot of FIG. 1B shows that fluid conductance goes to zerowhen the occlusion component 103 is activated for full occlusion. Thisdefinition is independent of the pressure gradient/difference(F=G(Pa−Pb)). The plot of FIG. 1C depicts the conditions for the fluidconductance (G₀) versus time during a controlled partial occlusion,where an occlusion component according to the principles herein isactivated during a time period Δt. As shown in FIG. 1C, the conductancedoes not go to zero but rather goes to a minimum conductance level thathas magnitude greater than zero.

A catheter can be deployed in a wide variety of target locations in thevasculature. However, it is very difficult to precisely control thediameter of the vasculature at the target location. If there is noocclusion element or the occlusion element is not deployed, the leakageflow may be large, and the leakage flow may then prevent optimal controlof the forward (distal region) fluid flow. This is subject to therestriction that the flow is larger in larger diameter arteries, andsmaller if the artery is smaller. On the other hand a full occlusion cancause a dead zone to form. According to the principles herein, a smallcontrolled leakage flow structure can be used with the occlusioncomponent, so that the dead zone is flushed but the leakage is limitedso that it does not distort the valuable control of distal flow from useof the device. For a flow rate similar to blood flow in the carotid orfemoral arteries a forward flow rate of 200-500 ml/min would be veryuseful but a flushing flow rate of 20-50 ml/min or even less can beadequate to flush the dead zone.

As described herein, the minimum conductance level can be afixed-constant or a fixed-average value. For the fixed-constant, thefluid conductance G₀ is constant over time. For the fixed-average, theminimum conductance can be time-varying on a time scale t that is smallas compared to the time of overall device activation. In an example, abiased valve can be configured to achieve the controlled partialocclusion such that the conductance varies over a heartbeat. In thisexample, “fixed-average” refers to a fluid conductance that varies invalue during the time cycle of a heartbeat, but that has a non-zeroaveraged value over that heartbeat. This leads to a non-zero averagedfluid conductance over longer time periods.

In an example, the imposed minimum conductance is achieved in afixed-constant form. An imposed minimum conductance component located atthe distal tip of an extracorporeal injection member is configured tomaintain a minimal conductance that provides a flow of fluid to flushthe dead-zone that would otherwise be created by any complete occlusion.The size in flow resistance terms of that minimal conductance is setsuch that the flushing flow is not more than about 50%, or preferablynot more than about 10%, of the flow the device being used to directthrough the injector member.

In an example, the imposed minimum conductance is achieved in a passiveform. An example occlusion element is configured to include analternative fluidic bypass pathway, allowing a bypass flow to flush thedead-zone that would otherwise be created by the occlusion. The size inflow resistance terms of that bypass is set such that the bypass flow isnot more than about 50%, or preferably not more than about 10%, of theflow the device being used to direct through the injector member.

In some examples, the occlusion component can include soft balloons tobe used for the occlusions. In an example, the soft balloons maypartially be inflated, leading to some leakage conductance. This can beuseful since the vasculature is uneven and the amount of leakageconductance with a partial inflation is not observable to the userand/or controllable.

FIG. 2A shows a schematic of an example extracorporeal circuit 200 thatis coupled to an individual. The example extracorporeal circuit 200includes a pump system 206, a heat exchanger 208, and an injector member210. An example extracorporeal circuit can include two connections tothe vasculature of a patient. Such an example extracorporeal circuit canbe implemented to pump blood from the vasculature using one connectionand returns blood to the vasculature using the other connection. Anexample extracorporeal circuit can be used where the heart isinoperative or not supplying sufficient blood flow, or may be used tomodify blood and return to systemic flow or to a local region. Othermodifications may include oxygenation, dialysis, thermal, removal ofbacterial contaminants, removal of cancer causing cells, and others.FIG. 2A shows the injector member 210 coupled to the vasculature of thebody of an individual at vascular injection point 212, to return blood214 to the body based on a flow rate modulated using pump system 206.The most distal location in the vasculature at which blood is injectedinto the body is referred to herein as the “vasculature injectionpoint”.

In one example, the injector member 210 can include an occlusioncomponent to separate blood flow on one side from fluid injected by anextracorporeal circuit through the device shaft on the other side. Thiscan create a zone of no flow or limited flow in a portion of thevasculature, i.e., a dead zone. The dead zone can be avoided if anocclusion system is sited at an exact position relative to the nearestvasculature branch, but it is not possible to guarantee such an exactplacement in practice in real patients. As a result, a dead zone isusually formed in the branch including the injection point where blooddoes not flow. This can potentially cause thrombus or blood clots toform if the occlusion is left in place for long periods of time.Extracorporeal blood supply circuits can be used for long periods oftime, such as but not limited to time on the order of hours to days,which can be sufficient time to increase the risk of formation ofthrombus or blood clots.

FIG. 2B shows an example injector member 210 that is a component of theexample extracorporeal circuit system of FIG. 2A that returns blood to aspecific location in the body vascular injection point 212. Injectingfluid 216 through shaft lumen can add to blood flow in this branch. Tothe extent that alternative blood flow is blocked, the injected bloodmay dominate the flow in the distal vasculature.

FIG. 2C shows an example injector member 210 that is a component of theexample extracorporeal circuit system of FIG. 2A that returns blood(injecting fluid 216) to a specific location in the body. The injectormember 210 is coupled to an occlusion component 203 that is shown tofully occlude a portion of the vasculature. As shown in FIG. 2C, whenthe injector member 210 injects blood at a vascular injection pointthrough the occlusion device 203, a dead zone 205 can form proximate tothe occlusion component 203.

FIGS. 3A-3B show example imposed minimum conductance systems accordingto the principles herein. The imposed minimum conductance system of FIG.3A includes a lumen 320, having a discrete length l, that is disposedalong the shaft of the device and under a component 321 (such as but notlimited to a soft balloon 321), so that it provides a minimumconductance for flow to flush the dead zone. Such a lumen 320 controlledby the design length and the diameter can present a constant flow ratefor the fluid and therefore allows a small bypass flow. FIG. 3A showsthe forward direction of new flushing flow 324 through lumen 320. FIG.3B shows the backward direction of flushing flow 326 (flushing flowretrograde) through lumen 320. Dashed lines in FIGS. 3A-3B are used toshow the direction of blood flow 328. In both FIG. 3A and FIG. 3B, fluidflowing through the minimal conductance can serve to flush the dead zoneproximate to the component 321, thereby preventing or minimizingunwanted thrombus formation.

FIGS. 4A-4B show another example imposed minimum conductance systemaccording to the principles herein. Rather than an extra lumen under theimposed minimum conductance component (as shown in FIGS. 3A-3B), FIGS.4A-4B show example imposed minimum conductance systems that include oneor more holes or orifices 430 in the shaft of the device, just proximalto the component 421 (such as but not limited to a balloon). In theseexample systems, a fraction of the flow 424 that the device directstowards its distal tip leaks out through the one or more holes (ororifices) 430 prior to reaching the occlusion. FIG. 4A also shows thedirection of blood flow 428. FIG. 4A illustrates an example when thevalue of pressure Pb is smaller than pressure Pa, which results in abackward flush flow (illustrated as flow 424). FIG. 4B shows the exampleimposed minimum conductance system for a scenario where Pb is largeenough relative to than Pa such that a forward flush flow 426 results.

FIG. 4C shows another example imposed minimum conductance systemaccording to the principles herein. The example imposed minimumconductance system includes an imposed minimum conductance component (aspring driven membrane 440) including one or more holes (or apertures)431. The one or more holes (or apertures) 431 are used to control fluidflow, and provide the minimum conductance. In the example imposedminimum conductance system of FIG. 4C, membrane 440 is illustrated incross-section. However, membrane 440 includes one or more substantiallysolid membrane portions deployed symmetrically about the device shaft(similarly to the deployment of an umbrella). FIG. 4C also shows thedirection of blood flow 428 and the fraction of the fluid flow 442 thatleaks out through the one or more holes (or apertures) 431 of theimposed minimum conductance component.

FIGS. 4D(i) and 4D(ii) show other example imposed minimum conductancesystems according to the principles herein. The example system of FIG.4D(i) includes a multi-lobed soft balloon (or other structured balloon)450 that includes gaps in sealing the vasculature, between the lobes ofthe balloon, to provide the minimum conductance. In various examples,the multi-lobed soft balloon (or other structured balloon) 450 can beformed with two, three or more lobes. FIG. 4D(ii) shows cross-sectionviews (through line A-A′ shown in FIG. 4D(i)) of different examples of amulti-lobed soft balloon (or other structured balloon) 450. Asnon-limiting examples, the imposed minimum conductance system caninclude a two-lobed soft balloon (or other two-lobed structured balloon)455 that includes gaps 460, or a three-lobed soft balloon (or otherthree-lobed structured balloon) 465 that includes gaps 470.

FIGS. 5A(i)-C show other example imposed minimum conductance systemsaccording to the principles herein. In the example system of FIG. 5A, abiased valve 550 is used to add control of the direction of flushingflow to the minimum conductance. Therefore, the directionality mightcreate a fixed-constant flow in the direction supported by the pressuredifference across the means. As an example, the pressure difference inthe vasculature can be such that the shift in blood pressure at theinjection point branch due to each heart beat changes sign, i.e.,changes from a positive pressure value to a negative value based onsystolic/diastolic pressure variation. The example imposed minimumconductance system can be configured such that, based on the sign (i.e.,direction) of the pressure differential, the flushing flow may be ‘on’during only a portion of the heartbeat cycle, achieving a“fixed-average” minimum conductance rather than a “fixed-constant”minimum conductance.

FIG. 5A(i) shows an example imposed minimum conductance system thatincludes a biased valve 510 on an aperture in a catheter lumen thatincludes a component 521 (such as but not limited to a soft balloon).The parameters P_(in) and P_(out) are values of pressures inside thelumen and outside, proximal to the soft balloon 521. In this example,the distal region is the region where the flow rate and pressure aredominated by the flow passed through the lumen and injected through thedistal tip. In general, if P_(out) is driven by the heart, the value ofP_(out) has a similar cycle as the heart beats, reaching a local maximumand minimum in each cycle. FIG. 5A(ii) shows an example biased valvethat can be implemented in the example system of FIG. 5A(i). FIG. 5A(ii)shows an example biased valve 510 mounted to portion of the shaft of acatheter, with a hole coupling the inside lumen of the shaft to theexterior and a flexible plastic flap, larger than the hole and anchoredon at least one side, overlaying the hole. The example biased valve isconfigured such that a positive pressure difference (pressure insideshaft greater than pressure outside) can cause the flexible plastic flapto open, allowing fluid to flow outwards, and a negative pressuredifference (pressure inside shaft lower than pressure outside) causesthe flexible plastic flap to close and seal against the edges of thehole, blocking inward flow of fluid.

FIG. 5B shows an example imposed minimum conductance system thatincludes a biased valve 532 coupled to a component 521. The biased valve532 includes a flap that is configured to open and allow flow of fluidout of the central lumen of the injection member, but not allow flowinto the lumen. That is, the biased valve 532 allows flow 534 when thevalue of pressure P_(b) is lower than pressure P_(a), which occursduring certain time intervals of the heartbeat cycle. FIG. 5B shows thefraction of the flow 534 through the flap of the biased valve 532 andthe direction of blood flow 538. In this example, only a small fractionof blood injected into the body from the extracorporeal circuit is usedto flush the dead zone (i.e., the flow 534 through the biased valve).

FIG. 5C shows an example imposed minimum conductance system thatincludes a flap acting as a biased valve 540 on an end of a bypass lumen542. The lumen 542 has a discrete length l, and is disposed along theshaft of the injector member and under the component 521, similar to theimposed minimum conductance systems shown in FIG. 3A or FIG. 3B. Thecoupled action of the biased valve 540 and the bypass lumen 542 providea minimum conductance for flow to flush the dead zone (or low-flowzone). FIG. 5C shows the fraction of the flow 544 through the flap ofthe biased valve 540 and the direction of blood flow 548. The flap ofthe biased valve 540 could be mounted on either the proximal end ordistal end of the bypass lumen 542, thereby allowing the direction offlushing flow to be selected by design. That is, if a flap configured toallow fluid conduction only outwards is mounted at the proximal end oflumen 542 (as shown in FIG. 5C), the distal injected blood flows back toflush. If the flap is mounted at the distal end of lumen 542, the normalblood flow from the branch flushes forward and mixes with the injectedblood at the vascular injection point. The detailed operation is partlydictated by the applied pressure difference between the P_(b) (pressurebefore the lumen 542) and P_(a) (pressure after the lumen 542), as thebiased valves can be configured to allow flow in only one direction.This example implementation would be beneficial if the values ofpressure P_(a) and P_(b) are sufficiently close such that changes inP_(b) from the systolic/diastolic pressure change with the heartbeatcauses the biased valve to open during certain time intervals in eachheart cycle.

According to the principles herein, an example imposed minimumconductance component, or an example system including a imposed minimumconductance component, can be used for providing selective thermaltherapy. The example imposed minimum conductance component can becoupled to any system that is configured to apply a selective thermaltherapy. In any example implementation, the imposed minimum conductancecomponent according to the principles herein can be used in place of theusual occlusion element. The imposed minimum conductance component canbe disposed proximate to the distal tip of at least one injector memberan injector member of the system for applying the selective thermaltherapy. As non-limiting examples, an imposed minimum conductancecomponent according to the principles herein can be coupled to anysystem for applying selective thermal therapy in the art, such as thesystem disclosed in U.S. Pat. No. 7,789,846 B2, or international (PCT)Application No. PCT/US2015/033529.

In any example herein, the imposed minimum conductance component can beformed with an atraumatic surface, a hydrophilic coating, or a drugcoating, or any combination thereof.

FIG. 6A shows an example controlled flow partitioning system of thepresent disclosure. The example controlled flow partitioning systemincludes a first pressure sensor 610 and a second pressure sensor 612.The first pressure sensor 610 can be disposed proximate to the tip ofthe injector member 614 of a catheter, and the second pressure sensor612 can be disposed on the injector member 614 at a pre-definedseparation (Δ) proximal to an operator as measured from the tip (or frompressure sensor 610). As non-limiting examples, the pre-definedseparation (Δ) can be about 2 cm, about 5 cm, about 8 cm, about 12 cm,about 15 cm, about 20 cm, about 25 cm, or about 30 cm. In variousnon-limiting examples, one or both of pressure sensors 610 and 612 canbe implemented as silicon-based sensors embedded in the catheter wall(with electronic (wired) readout), or optical fiber-based pressuresensors that use fibers in lumens in the catheter wall to providereadout to appropriate computing interface systems at the proximal endof the catheter. In another example implementation, one or both ofpressure sensors 610 and 612 is configured to use a simple wall lumen,having distal opening at the location as illustrated in FIG. 6A, filledwith an incompressible fluid, and an external pressure sensor mounted ona fluid connector at the proximal end of the catheter to measure thestatic or low frequency pressure conducted by the fluid column of thelumen. Pressure sensor 610 can be configured to measure the pressureproximate to the tip (P_(tip)) and pressure sensor 612 can be configuredto measure the pressure (P_(b)) proximate to the injector member 614.FIG. 6A also shows examples of the direction of blood flow at flow rateF_(b) around the catheter and the injected blood flow at flow rateF_(tip) at the tip of the injector member.

As also shown in FIG. 6A, the catheter can be coupled to a flow ratesource 616 of an extracorporeal system. In an example implementation,the fluid can be volume flow driven rather than being pressure driven.When fluid is injected into the vasculature through the tip (F_(tip)),it mixes with fluid from upstream (F_(b)) and flows through thedownstream conductance G_(tip). The upstream flow passes through theconductance G_(b), shown in FIG. 6A as occurring in the space betweenthe wall of the artery (or vein) and the catheter. It can be difficultto measure or predict directly a value for conductance G_(b). Even withthe pressure sensors 610 and 612 being disposed to measure P_(b) andP_(tip), it can be difficult to measure F_(b) directly if G_(b) isunknown. Example systems and methodologies according to the principlesherein can be used for determining a value for G_(b).

In an example, the flow rate source can be used to control a volumetricflow rate. The example flow rate source can be, but is not limited to, adisplacement pump, a syringe pump, or a rotary pump.

In an example, the flow rate source can be used to control the flow ratesuch that fluid injected at the distal tip flows as a series of volumeimpulses. In this example, the series of volume impulses can be modeledaccording to a step function. The flow rate source can be a pump thatexecutes instructions from a processing unit of a console to delivereach of the impulses of the series of impulses, or a pump that isinitiated based on a first signal from the console and continuallydelivers the step function impulses until a second signal from theconsole causes the pump to cease operation.

In other examples, the flow rate source can be used to control the flowrate such that fluid flows according to other types of functional forms,such as but not limited to a sinusoidal, sawtooth, or otherwise cyclicalfunctional form.

In any example herein, the flow rate source can be used to control theflow rate to establish the flow rate pattern. As described above, theflow rate pattern can be based on an arbitrary waveform or other typesof functional forms, such as but not limited to a sinusoidal, sawtooth,or otherwise cyclical functional form.

In a non-limiting example according to the principles of FIG. 6A, aninjector member is coupled to two pressure sensors, with the injectormember being driven by an external flow rate controlling means to allowmeasurement or computation of values for the proximal exteriorconductance and the distal exterior conductance. The example systemenables deduction of flow around the injector member of the catheterfrom data indicative of pressure measurements.

A controlled flow partitioning system is provided for determining thetwo conductances, including the system illustrated in FIG. 6A. The firstconductance, referred to as the proximal conductance (G_(b)), is theconductance in the vascular space outside the catheter between theplanes defined by the two pressure sensors 610 and 612. The secondconductance, referred to as the distal conductance (G_(tip)) is theconductance from the tip to blood return to the core system (or groundin a flow sense). Both of these conductances generally are not deduciblewithout measurement, since the computation would use data indicative ofthe size and shape of the local vasculature. In the case of G_(tip),computation would use data indicative of the state of and/or the amountof damage of the vasculature bed. Knowledge of values of both of theseconductances may offer clinical benefit, since they represent ameasurement of the local state of vasodilation/vasoconstriction of thepatient. Using the pressure sensors 610 and 612 to measure P_(b) andP_(tip), if the conductance between them is a controlled one as in theprior described imposed minimum conductance, then the flow can beestimated using flow F_(b)=G_(b)(P_(b)−P_(tip)). In an exampleimplementation where the computation of G_(b) includes data indicativeof the surface of the vein or artery, it may not be possible todetermine G_(b) beforehand. In general, G_(tip) cannot be determinedprior to an operation or other medical procedure that involves placementof the injection member.

Example systems and methodologies are provided herein for computing bothG_(b) and G_(tip) in situ for a patient during an operation or othermedical procedure. Using a linear approximation, balancing the flowaround the distal tip of the injection member can be expressed using twoequations as follows:F _(b) =G _(b)(P _(b) −P _(tip))  (1)(F _(b) +F _(tip))=G _(tip)(P _(tip))  (2)The value for F_(tip) can be set from the pump (such as but not limitedto flow rate source 616). The example system of FIG. 6A can be used tomeasure values for pressure P_(b) and pressure P_(tip). Using thesevalues, the equations can be reduced to:G _(tip) =F _(tip) /P _(tip) +Gb(P _(b) −P _(tip))/P _(tip)  (3)where Gtip and Gb are the unknowns. During an operation or other medicalprocedure that uses the injection member to return blood to the body,the initial injected flow at time T₀ can be used as F′_(tip) (as anon-limiting example, about 250 ml/min). At time T₁ that value of flowmight be changed to F″_(tip) (as a non-limiting example, about 275ml/min, a 10% increase). These non-limiting example values of flow attimes T₀ and T₁ can be chosen to fall within a desirable clinical rangefor the specific anatomy at the injection point and the specificclinical application. The example system of FIG. 6A can be used tomeasure values for pressure P_(b) and pressure P_(tip) at the timepoints T₀ (P′_(b) and P′_(tip)) and T₁ (P″_(b) and P″_(tip)). Using thefour different values of pressure and two different values injectionflows in equation (3), i.e., introducing F′_(tip), P′_(tip), P′_(b) attime T₀ and F″_(tip), P″_(tip), and P″_(b) at time T₁, generates two (2)equations, each with two (2) unknowns. These equations can be used tocompute values for G_(b) and G_(tip). It is readily apparent to one ofordinary skill in the art that equations (1), (2) and (3) arenon-limiting examples of equations relating flow, conductance, andpressure in a vascular region. Other equations, including more complexversions of the equations, can be applicable. For example, equations inwhich conductance is not independent of pressure, but itself is afunction of pressure, may also be addressed by using repeatedmeasurements of the pressures at different values of applied flowF_(tip), to establish more equations and allow solving for forms ofconductance (G) that are linear, or even quadratic, or higher orderfunctions of pressure.

As described herein, the flow rate source can be used to control theflow rate such that fluid injected at the distal tip flows according toa step function, or other types of functional forms, such as but notlimited to a sinusoidal, sawtooth, or otherwise cyclical functionalform. In other examples, the flow rate can be modeled based onmeasurements of a response function with fluid flow, and solving for anapplicable functional form.

Example systems and methodologies are provided herein for computing bothG_(b) and G_(tip) in situ for a patient during a lengthy operation orother medical procedure. As a non-limiting example, such a lengthyoperation (or other medical procedure) could last on the order of hoursto days. An example methodology can include applying a step change toF_(tip) (i.e., a discrete change in value from a baseline) for a shortinterval of time (t₁) at regular repeated cycles during the operation orother medical procedure. As a non-limiting time the step change can beapplied to F_(tip) for the first 5 minutes (i.e., t₁=5 minutes) of eachhour of the operation or other medical procedure. At the end of timeinterval t₁, the value of F_(tip) is returned to the baseline value.This example methodology for modifying the value of F_(tip) can be usedfor measuring G_(b) and G_(tip) at each hour during the lengthyoperation or other medical procedure, using the methodologies describedherein. These example systems and methodologies have clinicalapplication in monitoring the vascular state(vasodilation/vasoconstriction) or detecting the process of thrombusformation or time of thrombolysis.

Another example clinical application of the example systems andmethodologies is as follows. During an operation or other medicalprocedure, with values computed for G_(b) and G_(tip), the quantity offlow F_(b) that is flushing the space proximal to the tip can bedetermined from the measured pressure P_(b) and P_(tip). If flow F_(b)falls out of a desired range of values, F_(tip) may be adjusted toadjust F_(b).

Another clinical application of the systems and methodologies isdetermination of the heat capacity of the blood applied to the tissue.During the operation or other medical procedure, F_(b) and F_(tip) canmix in the zone distal to the tip. If the blood flow F_(b) is at a firsttemperature and the blood flow injected F_(tip) is at a secondtemperature different than the first temperature, then the heat capacityof the blood applied to the tissue in the distal zone may be calculateddirectly and adjustment of the temperature of the injected blood may beused to compensate for warm or core blood flow F_(b). Alternatively, theprocess of controlled rewarming may be done by adjusting the ratio offlows F_(b):F_(tip), as well as their temperature difference. An examplemethodology for measuring G_(b) and G_(tip) described herein can beapplied a single time or multiple times during an operation or othermedical procedure. The method can be generalized to use more than onestep change in F_(tip) in which case the operator can measure values forG_(b) and G_(tip) to determine how they might vary out of the linearapproximation of equations (1-3). An operator can implement an examplemethodology according to the principles herein by, e.g., directlysetting F_(tip), recording the sensor recordings, and using a computingdevice to perform the computations. In another example implementation, acomputing device or system herein can include at least one processingunit that is programmed to execute processor-executable instructions, tocause a controller of an example system to implement the measurementroutine automatically as described herein for measuring values for G_(b)and G_(tip). The example system can be configured to allow a user to seta nominal value of F_(tip) and execute processor-executable instructionsfor performing an automatic measurement of G_(b) and G_(tip) at thedesired time intervals, such as but not limited to, every 30, or 45, or60 minutes or other time interval. In any example herein, the computingdevice can be a console.

FIG. 6B shows an example controlled flow partitioning system accordingto the principles herein. The example system includes two pressuresensors in use with a concentric cylinder two-port catheter to supportan independent local extracorporeal loop. As shown in FIG. 6B, twopressure sensors 610′ and 612′ are coupled to an insertion member 614that is part of an extracorporeal circuit access catheter of concentricshaft type. In the example, the outer shaft 618 supplies blood to theextracorporeal circuit 618 and the inner shaft 614 acts as an injectionmember to return blood to a location in the body. FIG. 6B also showsdashed line 615 for blood flow out to the extracorporeal circuit anddashed line 617 for blood flow around a catheter (Fb). As non-limitingexamples, U.S. Pat. Nos. 7,704,220 and 7,789,846, disclose examples ofconcentric extracorporeal access catheters that can be implemented inone or more example systems according to the principles herein.

FIGS. 6C and 6D show example systems that can be used to compute valuesof conductance in a region of the vasculature proximate to the heart,according to principles herein. In the examples of FIGS. 6C and 6D, theexample system is shown disposed in a region of the aortic arch. Asshown in FIG. 6C, the example system includes pressure sensors 610 and612 coupled to a catheter member 620. In this example, the pressuresensor measurements can be used to compute the conductance as describedherein. In an example, using the pressure measurements, the conductancecan be computed according to the example method described hereinabovefor computing both G_(b) and G_(tip) in situ. In the example of FIG. 6C,fluid flow can be introduced fron a distal tip of the catheter member620. FIG. 6D shows another example system that is similar to FIG. 6C,with the exception that the catheter 620 includes a proximal port 622that allows fluid flow from a more intermediate region of the cathetermember 622.

In any example system, method, device, and apparatus herein, the fluidinjected through the injector member of may be mixed with the fluidpassing through the exterior space around the catheter or device(exterior fluid). If the fluid flows mix, they form a mixed fluid in theregion distal to the point of injection (also referred to herein as amixed distal flow). If a drug or pharmacological agent of a knownconcentration (in mg/ml or other units of mass/volume) is added to theinjected fluid, the concentration of drug or pharmacological agent inthe distal mixed fluid is unknown, unless the ratio of the exteriorfluid and injected fluid flow rates is known. The example systemsdescribed herein can be used to set the exterior conductance (imposedminimum conductance component) or quantify the exterior conductance(controlled partitioning flow system). Based on the conductance data,the exterior fluid flow rate can be measured or computed. With thecomputed value of exterior fluid flow rate, and the injected flow rateset by the pump system (or other system) coupled to the injector member,the concentration of drug or pharmacological agent added to the injectedfluid can be adjusted to achieve the desired concentration of drug inthe distal fluid mixture.

In any example herein, the drug or pharmacological agent can be anysubstance used to diagnose, cure, treat, or prevent a disease. Forexample, the drug or pharmacological agent can include an electrolytesolution, nanoparticles, biological agent, small molecule, largemolecule, polymeric material, biopharmaceutical, or any other drug orpharmacological agent that can be administered in the blood stream.

An example system according to the principles herein can be used forproviding at least two zones of selective thermal therapy. The examplesystem includes an extracorporeal circuit. The example extracorporealcircuit includes an injector member including a distal tip disposed at avascular location, an imposed minimum conductance component disposedproximate to the distal tip. The example system can also include a firstport to withdraw blood from the body, a second port to return blood tothe body, a first pump disposed between the first port and the secondport to pump blood from the first port to the second port, a branchingsection positioned between the first pump and second port, a third portcoupled to the branching section, the third port being positioned on anextracorporeal side of the injector member, and a second pump positionedbetween the branching section and the third port. The second pump can beconfigured to control a flow rate out the branching section into theinjector member through the third port. The example system can alsoinclude a first heat exchanger disposed between the first port and thesecond port, and a second heat exchanger disposed between the secondpump and the injector member. The first heat exchanger can be configuredto set a temperature of blood injected into the second port to a firsttemperature level. The second heat exchanger can be configured to setthe temperature of blood injected into the injector member to a secondtemperature level different from the first temperature level. The firstheat exchanger can be disposed between the branching section and thefirst port or between the branching section and the second port.

The example system for providing at least two zones of selective thermaltherapy can include an occlusion component, or an imposed minimumconductance component, disposed proximate to the distal tip of theinjector member.

Another example system for providing at least two zones of selectivethermal therapy according to the principles herein can include anextracorporeal circuit including an injector member comprising a distaltip disposed at a vascular location. The example system can furtherinclude a controlled flow partitioning system proximal to the distaltip. The controlled flow partitioning system can include a first sensorfor measuring flow proximate to a distal tip of the at least oneinjector member and a second pressure sensor for measuring a secondpressure, the second pressure sensor being disposed proximal from thedistal tip, at a distance greater than or approximately equal to twice adiameter of the vasculature. In other examples, the separation distancecan be greater than or approximately equal to three, five, or ten timesthe diameter of the vasculature. In another example, the separationdistance can be greater than about 1.0 cm proximal from the distal tip.The example system can also include a first port to withdraw blood fromthe body, a second port to return blood to the body, a first pumpdisposed between the first port and the second port to pump blood fromthe first port to the second port, a branching section positionedbetween the first pump and second port, a third port coupled to thebranching section, the third port being positioned on an extracorporealside of the injector member, and a second pump positioned between thebranching section and the third port. The second pump can be configuredto control a flow rate out the branching section into the injectormember through the third port. The example system can also include afirst heat exchanger disposed between the first port and the secondport, and a second heat exchanger disposed between the second pump andthe injector member. The first heat exchanger can be configured to set atemperature of blood injected into the second port to a firsttemperature level. The second heat exchanger can be configured to setthe temperature of blood injected into the injector member to a secondtemperature level different from the first temperature level. The firstheat exchanger can be disposed between the branching section and thefirst port or between the branching section and the second port.

The example system for providing at least two zones of selective thermaltherapy can include an occlusion component, or an imposed minimumconductance component, disposed proximate to the distal tip of theinjector member.

FIG. 7A shows a schematic of an example three-port extracorporealcircuit for providing at least two zones of selective thermal therapyaccording to the principles herein. As a non-limiting example, theextracorporeal circuit can be implemented for controlling blood flow tothe core and an attached local branch, with independent flow rate andtemperature control. In the non-limiting example of FIG. 7A, theextracorporeal system 700 is a three port, two-zone, extracorporealcircuit in which a main veno-arterial (VA) extracorporeal loop 710 takesblood from the body via a first port 711 and returns it using a pump 712and oxygenator/heat exchanger 714 via a second port 715. The examplesystem can include a displacement or volume driven pump 716 located on abranch 718 of the main loop and pulls a controlled volume flow rate ofblood out of the main circuit and injects it through an independent heatexchanger 720, a third port 721, and the distal injector member 722 to alocal region 724 of a body. In a non-limiting example, branch 718 can bea local perfusion hypothermia branch. The non-limiting example system ofFIG. 7A allows establishment of two independently controlled temperaturezones in the body when deployed with appropriate zone temperaturesensors. In other examples, the branch 718 can be coupled to main loopeither before or after the main loop oxygenator 714, depending on theusers desire for the injector member blood to be oxygenated or not. Inthese examples, if the system is used to apply localized hypothermiathrough the distal injector member, such as disclosed in International(PCT) Application No. PCT/US2015/033529, the absence of a concentriccylinder outflow on the injector member may cause an increase in theconductive cooling of that member catheter to the artery it is placedwithin. This effect may require some additional warming on the maincircuit loop to achieve equivalent thermal targets in the body zonesthat are desired to be controlled.

FIG. 7B shows another example extracorporeal circuit for providing atleast two zones of selective thermal therapy according to the principlesherein. Similarly to FIG. 7A, the extracorporeal system 700′ of FIG. 7Bincludes a main VA extracorporeal loop 710 that takes blood from thebody via a first port 711 and returns it using a pump 712, an oxygenator713 and a heat exchanger 714 via a second port 715. In a non-limitingexample, the oxygenator 713 and heat exchanger 714 can be a combinedunit. The example system 700′ also include a displacement or volumedriven pump 716 located on a branch 718, to pull a controlled volumeflow rate of blood out of the main circuit and inject it through anindependent heat exchanger 720, a third port 721, and a distal injectormember 722 to a local region of a body. In the example theextracorporeal system 700′, the injector member can also include anocclusion means, an imposed minimum conductance component (according toany of the examples herein, including any of FIGS. 3A to 5C), or apressure sensor pair coupled to the injector member (according to any ofthe examples herein, including FIG. 6A or 6B), or both a pressure sensorpair and either an occlusion means or an imposed minimum conductancecomponent. In the non-limiting example system of FIG. 7B, the injectormember 722 includes both a imposed minimum conductance component 726 anda coupled pressure sensor pair 728. In the example of FIG. 7B, theoxygenator 714 on the main loop is positioned before the local injectorbranch 718 and so the local injected blood is oxygenated.

FIG. 7C another example extracorporeal circuit for providing at leasttwo zones of selective thermal therapy according to the principlesherein, which includes similar components to those described inconnection with FIG. 7B. However, in the extracorporeal system 700″ ofFIG. 7C, the oxygenator 713 on the main loop is positioned along theloop after the local injector branch, and so the local injected blood isnot directly oxygenated. In a non-limiting example, the oxygenator 713and heat exchanger 714 can be a combined unit.

The non-limiting example system of any of FIG. 7A-7C can includetemperature sensors coupled to regions of the body to allow providemeasurement of temperature at the two independently controlledtemperature zones in the body. For example, at least one temperaturesensor can be disposed at or otherwise coupled to the region perfused bythe second port and at least one temperature sensor can be disposed ator otherwise coupled to the local region of the body perfused by thedistal injector member. The at least one temperature sensor disposed ator otherwise coupled to the region perfused by the second port can beconfigured to measure an average core body temperature and/or averagesystem temperature of a portion of body. The at least one temperaturesensor disposed at or otherwise coupled to the local region of the bodyperfused by the distal injector member configured to measure thetemperature of the local region.

The non-limiting example system of any of FIG. 7A-7C can includetemperature sensors coupled to at least one of the heat exchangers.

Other non-limiting example systems according to the principles of FIGS.7A-7C can be configured for performing other procedures on the blood inthe extracorporeal loops, such as but not limited to dialysis,oxygenation, purification, pharmacological manipulation, photolysis, orother procedures that can be useful on blood. Any one or more of theseprocedures could be performed on either the main loop or the branch orboth (with differing amounts or quantities of one or more of theprocedures being performed on the loop or the branch).

In the non-limiting examples of FIGS. 7A-7C, the maim loop is describedas a VA loop. However, in other example implementations, the main loopcan be a veno-venous (VV) loop instead of a VA loop. In an example VVloop, the blood is taken from the venous side of the vasculature,typically from the iliac or inferior vena cava, and returned into thevena cava, typically higher or closer to the heart. In another example,the VV may be implemented with a single puncture in the femoral vein,and a single dual lumen catheter can be used to place both the VV loopblood output and return, each using a lumen of the catheter.

An example system according to the principles herein can include one ormore control consoles. The example consoles can include one or more userinterfaces, configured to receive input representative of desiredsettings for one or more of the pumps, heat exchanges, and/oroxygenators of the example extracorporeal system main loop and/or localbranch. The example console can include one or more processing units toexecute processor-executable instructions to cause one or more of thepumps, heat exchanges, and/or oxygenators to change to a differentsetting of operation, and/or to maintain a particular setting ofoperation, over a period of time. In any example, the input can bereceived at the one or more user interfaces directly from a user or fromanother computing device. The example console can include at least onememory to store processor-executable instructions that can beimplemented using the one or more processing units. The example consolecan be configured to store and/or transmit data indicative of thesettings of the system and/or any measurement data derived based onexecution of one or more procedures using the example system coupled tothe console.

FIG. 8A shows an example extracorporeal circuit system 800 coupled to aconsole 802, according to the principles herein. Similarly to FIG. 7B,the extracorporeal system 800 of FIG. 8A includes a main VAextracorporeal loop 810 that takes blood from the body via a first port811 and returns it via a second port 815 using a pump 812, an oxygenator813 and a heat exchanger 814. In a non-limiting example, the oxygenator813 and heat exchanger 814 can be a combined unit. The example system800 also include a displacement or volume driven pump 816 located on abranch 818, to pull a controlled volume flow rate of blood out of themain circuit and inject it through an independent heat exchanger 820, athird port 821, and a distal injector member 822 to a local region of abody. Also similarly to the non-limiting example system of FIG. 7B, theinjector member includes a imposed minimum conductance component 826 anda pressure sensor pair 828. In the example of FIG. 8A, the console 802is coupled to the displacement or volume driven pump 816 located on abranch 818 and the pressure sensor pair 828. In other examples, theconsole 802 can be coupled to different components of the system,including to any one or more of the pumps, heat exchangers, and/oroxygenators of the example system.

The non-limiting example system of FIG. 8A can include temperaturesensors coupled to regions of the body to allow provide measurement oftemperature at the two independently controlled temperature zones in thebody. For example, at least one temperature sensor can be disposed at orotherwise coupled to the region perfused by the second port and at leastone temperature sensor can be disposed at or otherwise coupled to thelocal region of the body perfused by the distal injector member. The atleast one temperature sensor disposed at or otherwise coupled to theregion perfused by the second port can be configured to measure anaverage core body temperature and/or average system temperature of aportion of body. The at least one temperature sensor disposed at orotherwise coupled to the local region of the body perfused by the distalinjector member configured to measure the temperature of the localregion.

In an example, the console 802 can be configured as an operatingconsole. In this example, the operating console can include a waterchillers/heaters to drive the heat exchangers and a graphic userinterface configured to display user instructions for implementation ofoperational steps of an operating sequence. The graphic user interfaceof console 802 can be configured to implement the operating sequence tocause the extracorporeal circuit to control the temperature of the bloodperfused by the second port to adjust a temperature measurement reportedby at least one temperature sensor to stay within a core body targetrange, and cause the extracorporeal circuit to control the temperatureof the blood injected to the local region such that at least onetemperature sensor reports a temperature measurement within a targetregion temperature range.

The example console 802 can be configured to automate the performance ofthe Gb and Gtip measurement using the methodology of the controlled flowpartitioning system described herein. Based on input received, theconsole can cause a processor to execute instructions for recording dataindicative of the flow inside and values of pressure on the injectormember, while also controlling that amount of the injected flow rate, toaid in or enable automatic performance of the methodology of measurementof the proximal and distal conductances at the injector member accordingto the principles of any of the examples described herein. Such anexample console 802 can be configured to automate the controlled flowpartitioning system, where it is applied on the injector member coupledto a full extracorporeal loop, or to another catheter system with anextracorporeal volume flow rate source such as, but not limited to, theexample in FIG. 6A.

FIG. 8B shows another example system 850 coupled to a console 852,according to the principles herein. The example system 850 includes aflow rate control source 860 and reservoir 862. As a non-limitingexample, the example flow rate control source 860 and reservoir 862 canbe, but is not limited to, a syringe or syringe drive. The examplesystem 850 also includes a distal injector member 872 coupled to a localregion of a body. The injector member 872 includes a imposed minimumconductance component 876 and a pressure sensor pair 878. In the exampleof FIG. 8B, the console 802 is coupled to the flow rate control source860 and the pressure sensor pair 878. In the example of FIG. 8B, theflow rate control source 860 and reservoir 862 are used to establish thetwo Ftip settings of the controlled flow partitioning system (accordingto any of the examples described hereinabove). As a non-limitingexample, the settings based on instructions received at the console canbe to first withdraw blood to the reservoir at, e.g., 50 ml/min for 2minutes, then wait two minutes, then return blood at 50 ml/min for twominutes. In this non-limiting example, this establishes Ftip=−50 ml/min,Ftip=0, and Ftip=+50 ml/min. Based on input received at the console 852,e.g., from a user or another computing device, instructions can beexecuted to perform any other desirable procedure according to settingsspecified in the input.

An example system according to the principles herein can include one ormore controllers for controlling a flow of fluid. For example, the oneor more controllers can be coupled to an injection member to control theflow of fluid out of the distal tip of the injector member.

An example system according to the principles herein can include aconsole. FIG. 9 shows an example console 905, including at least oneprocessing unit 907 and a memory 909. An example console can include,for example, a desktop computer, a laptop computer, a tablet, asmartphone, a server, a computing cloud, combinations thereof, or anyother suitable device or devices capable of electronic communicationwith a controller or other system according to the principles herein.Example processing unit 907 can include, but is not limited to, amicrochip, a processor, a microprocessor, a special purpose processor,an application specific integrated circuit, a microcontroller, a fieldprogrammable gate array, any other suitable processor, or combinationsthereof. Example memory 909 can include, but is not limited to, hardwarememory, non-transitory tangible media, magnetic storage disks, opticaldisks, flash drives, computational device memory, random access memory,such as but not limited to DRAM, SRAM, EDO RAM, any other type ofmemory, or combinations thereof.

In an example, the console can include a display unit 911. Exampledisplay unit 111 can include, but is not limited to, a LED monitor, aLCD monitor, a television, a CRT monitor, a touchscreen, a computermonitor, a touchscreen monitor, a screen or display of a mobile device(such as but not limited to, a smartphone, a tablet, or an electronicbook), and/or any other display unit.

FIGS. 10A-10B show example methods that can be implemented using anexample flow partitioning system, or an example system including atleast two pressure sensors coupled to a catheter member, according tothe principles herein. One of more of the steps of FIGS. 10A-10B can beimplemented using a controller based on a command or other signal from aprocessing unit executing instructions stored to a memory.

FIG. 10A shows an example method that includes (step 1002) controllingthe flow of fluid injected at the distal tip of the injector member to apredetermined flow rate pattern over a time interval T, (step 1004)recording measurements of pressure using the first pressure sensor andsecond pressure sensor over the time interval T, and (step 1006)computing at least one of a proximal exterior conductance or a distalexterior conductance at the distal tip using data indicative of themeasurements of pressure, and the predetermined flow rate pattern. Thedistal tip can be a portion of an injector member of an extracorporealcircuit or a catheter member. In an example, the flow rate pattern canbe controlled using an injection flow rate source. In an example, theinjection flow rate source can be a pump.

FIG. 10B shows another example method that can be implemented using anexample flow partitioning system, or an example system including atleast two pressure sensors coupled to a catheter member, according tothe principles herein. In step 1052, the flow of blood injected at thedistal tip of an injector member (or catheter member) is controlled overa first time interval (T_(A)) to a first constant flow rate. In step1054, each of the first pressure sensor and the second pressure sensoris used to record at least a first measurement of pressure (P_(1A) andP_(1B)) during the first time interval (T_(A)). In step 1056, the flowof blood injected at the distal tip of the injector member is controlledover a second time interval (T_(B)) to a second constant flow ratedifferent from the first constant flow rate. In step 1058, each of thefirst pressure sensor and the second pressure sensor is used to recordat least a second measurement of pressure (P_(2A) and P_(2B)) during thesecond time interval (T_(B)). In step 1060, at least one processor ofthe processing unit is used to compute at least one of a proximalexterior conductance or a distal exterior conductance at the distal tipof the injector member (or catheter member) using data indicative of thefirst measurement of pressure, the second measurement of pressure, thefirst constant flow rate, and the second constant flow rate.

In an example, the example console can cause the display unit to displayan indication of the proximal exterior conductance, or the distalexterior conductance, or both, based on the computation.

In an example, the processing unit can also be caused to compute aprojection of at least one of a proximal exterior conductance or adistal exterior conductance over a third time interval (T_(C)) laterthan the first time interval (T_(A)) and the second time interval(T_(B)).

FIG. 11 is a block diagram of an example computing device 1110 that canbe used to implement an operation according to the principles herein. Inany example herein, computing device 1110 can be configured as aconsole. For clarity, FIG. 11 also refers back to and provides greaterdetail regarding various elements of the example system of FIG. 9. Thecomputing device 1110 can include one or more non-transitorycomputer-readable media for storing one or more computer-executableinstructions or software for implementing examples. The non-transitorycomputer-readable media can include, but are not limited to, one or moretypes of hardware memory, non-transitory tangible media (for example,one or more magnetic storage disks, one or more optical disks, one ormore flash drives), and the like. For example, memory 909 included inthe computing device 1110 can store computer-readable andcomputer-executable instructions or software for performing theoperations disclosed herein. For example, the memory 909 can store asoftware application 1140 which is configured to perform various of thedisclosed operations (e.g., causing a controller to control flow,recording a pressure sensor measurement, or performing a computation).The computing device 1110 can also include configurable and/orprogrammable processor 907 and an associated core 1114, and optionally,one or more additional configurable and/or programmable processingdevices, e.g., processor(s) 1112′ and associated core(s) 1114′ (forexample, in the case of computational devices having multipleprocessors/cores), for executing computer-readable andcomputer-executable instructions or software stored in the memory 909and other programs for controlling system hardware. Processor 907 andprocessor(s) 1112′ can each be a single core processor or multiple core(1114 and 1114′) processor.

Virtualization can be employed in the computing device 1110 so thatinfrastructure and resources in the console can be shared dynamically. Avirtual machine 1124 can be provided to handle a process running onmultiple processors so that the process appears to be using only onecomputing resource rather than multiple computing resources. Multiplevirtual machines can also be used with one processor.

Memory 909 can include a computational device memory or random accessmemory, such as DRAM, SRAM, EDO RAM, and the like. Memory 909 caninclude other types of memory as well, or combinations thereof.

A user can interact with the computing device 1110 through a visualdisplay unit 1128, such as a computer monitor, which can display one ormore user interfaces 1130 that can be provided in accordance withexample systems and methods. The computing device 1110 can include otherI/O devices for receiving input from a user, for example, a keyboard orany suitable multi-point touch interface 1118, a pointing device 1120(e.g., a mouse). The keyboard 1118 and the pointing device 1120 can becoupled to the visual display unit 1128. The computing device 1110 caninclude other suitable conventional I/O peripherals.

The computing device 1110 can also include one or more storage devices1134, such as a hard-drive, CD-ROM, or other computer readable media,for storing data and computer-readable instructions and/or software thatperform operations disclosed herein. Example storage device 1134 canalso store one or more databases for storing any suitable informationrequired to implement example systems and methods. The databases can beupdated manually or automatically at any suitable time to add, delete,and/or update one or more items in the databases.

The computing device 1110 can include a network interface 1122configured to interface via one or more network devices 1132 with one ormore networks, for example, Local Area Network (LAN), Wide Area Network(WAN) or the Internet through a variety of connections including, butnot limited to, standard telephone lines, LAN or WAN links (for example,802.11, T1, T3, 56 kb, X.25), broadband connections (for example, ISDN,Frame Relay, ATM), wireless connections, controller area network (CAN),or some combination of any or all of the above. The network interface1122 can include a built-in network adapter, network interface card,PCMCIA network card, card bus network adapter, wireless network adapter,USB network adapter, modem or any other device suitable for interfacingthe computing device 1110 to any type of network capable ofcommunication and performing the operations described herein. Moreover,the computing device 1110 can be any computational device, such as aworkstation, desktop computer, server, laptop, handheld computer, tabletcomputer, or other form of computing or telecommunications device thatis capable of communication and that has sufficient processor power andmemory capacity to perform the operations described herein.

The computing device 1110 can run any operating system 1126, such as anyof the versions of the Microsoft® Windows® operating systems, thedifferent releases of the Unix and Linux operating systems, any versionof the MacOS® for Macintosh computers, any embedded operating system,any real-time operating system, any open source operating system, anyproprietary operating system, or any other operating system capable ofrunning on the console and performing the operations described herein.In some examples, the operating system 1126 can be run in native mode oremulated mode. In an example, the operating system 1126 can be run onone or more cloud machine instances.

In non-limiting examples, computing device according to the principlesherein can include any one or more of a smartphone (such as but notlimited to an iPhone®, an Android™ phone, or a Blackberry®), a tabletcomputer, a laptop, a slate computer, an electronic gaming system (suchas but not limited to an XBOX®, a Playstation®, or a Wii®), anelectronic reader (an e-reader), and/or other electronic reader orhand-held computing device.

In any example herein, at least one method herein can be implementedusing a computer program. The computer program, also known as a program,software, software application, script, application or code, can bewritten in any form of programming language, including compiled orinterpreted languages, declarative or procedural languages, and it canbe deployed in any form, including as a stand alone program or as amodule, component, subroutine, object, or other unit suitable for use ina computing environment. A computer program may, but need not,correspond to a file in a file system. A program can be stored in aportion of a file that holds other programs or data (e.g., one or morescripts stored in a markup language document), in a single filededicated to the program in question, or in multiple coordinated files(e.g., files that store one or more modules, sub programs, or portionsof code). A computer program can be deployed to be executed on onecomputer or on multiple computers that are located at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

An example computing device can include an application (an “App”) toperform such functionalities as analyzing the temperature sensor data,pressure sensor data and computing the conductance, as described herein.As a non-limiting example, the App can be configured for download as a*.apk file for an Android™ compatible system, or as a *.app file for aniOS® compatible system.

An example console according to the principles herein can be used toimplement a control procedure for an operational sequence, such asdescribed in international (PCT) Application No. PCT/US2015/033529,which is incorporated herein by reference. For example, the console canincludes a display including a user interface, and chillers/heaters todrive the heat exchangers. The example console can be coupled to atleast one first temperature sensor positioned to measure an average corebody temperature and/or average system temperature of a portion of bodyperfused using the second port, and at least one second temperaturesensor positioned to measure the temperature of a local region perfusedby the injector member. The user interface configured to display userinstructions for implementation of operational steps of an operatingsequence. A non-limiting example console can include a user interfaceand computing device as defined herein to implement a semi-automatedcontrol procedure such that, in all phases of an operation, temperaturebands can be set in the apparatus and the system can alert the operatorto adjust the chiller temperatures if the sensor temperatures drift outof target bounds during each phase. A non-limiting example console caninclude a user interface and computing device as defined herein toimplement a fully automated control procedure such that, in all phasesof an operation, temperature bands can be set in the apparatus and thesystem can be configured to automatically adjust the chillertemperatures if the sensor temperatures drift out of target boundsduring each phase.

Any example system and method herein can be used to establish andcontrol two different temperature zones of at least portions of a bodyfor at least portions of a treatment procedure for a patient thatsuffered a local or global ischemic insult or circulation damage, suchas described in international (PCT) Application No. PCT/US2015/033529.An example method can include coupling a systemic perfusionextracorporeal circuit (SPEC) to the body using a peripheral placed loopand coupling a local perfusion extracorporeal circuit (LPEC) to bloodflowing within the vasculature to a local target region of the body(such as but not limited to the brain). The SPEC can includes a SPECinput flow port and a SPEC output flow port to be in contact with bloodflowing within the vasculature, a SPEC pump, and a SPEC heat exchanger.The LPEC can include a LPEC input flow port and a LPEC output flow portin contact with blood flowing within the vasculature, a LPEC pump, and aLPEC heat exchanger. The LPEC input flow port is disposed to perfuse thelocal target region of the body. The method includes positioning atleast one SPEC sensor to measure the average core body temperatureand/or average system temperature of the body perfused by the SPEC,positioning at least one LPEC sensor to measure the temperature of thelocal target region perfused by the LPEC, performing operational stepsof at least a minimum operating sequence, and implementing a controlprocedure to record measurements of the at least one LPEC sensor and atleast one SPEC sensor and to control independently a rate of blood flowand a heat exchanger temperature of the SPEC and LPEC, respectively. TheLPEC can include an injector member including a distal tip, disposed tobe in contact with blood flowing within the vasculature, where the LPECinjector member is disposed to perfuse the local target region of thebody. The LPEC can include an imposed minimum conductance component, ora controlled flow partitioning system, or both, according to theprincipled described herein. In an example where the LPEC includes acontrolled flow partitioning system, the LPEC pump can serve as aninjection flow rate source for the controlled flow partitioning system.

The LPEC input flow port can be disposed in contact with either the leftcommon carotid artery, right common carotid artery, or an arterydownstream of one of those locations.

In an example, the control procedure can cause the SPEC to control thetemperature of the blood injected by the SPEC to adjust the temperaturemeasurement reported by the SPEC temperature sensors to stay within atarget core body temperature range, and cause the LPEC to control thetemperature of the blood injected to the target region such that the oneor more LPEC temperature sensors report a temperature measurementaccording to a specified pattern of target region temperature values.The SPEC temperature sensors can be one or more of a bladder temperaturesensor or a rectal temperature sensor.

In another example, the control procedure can cause the SPEC to adjustthe systemic temperature of the body such that the one or more SPECtemperature sensors indicate an average temperature within the rangefrom about 32° C. to less than about 37° C., and cause the LPEC tocontrol the temperature of the blood to the target region such that theone or more LPEC temperature sensors indicate a temperature below about30° C. The control procedure can cause the SPEC to increase thetemperature of the blood to prevent the average temperature from fallingbelow about 32° C. The control procedure can cause the LPEC to cool thetemperature of the blood to a value within the range of about 10° C. toabout 30° C.

Any example system herein can include a control system programmed toexecute the control procedure. For example, the control system can beprogrammed to set a flow rate and a temperature at the LPEC pump andLPEC heat exchanger independently from a flow rate at the SPEC pump. Thecontrol system can be programmed to cause the LPEC to control thetemperature of the blood to the target region automatically, or based ona manual input. The control system can be programmed to cause the SPECto increase the temperature of the blood to prevent the averagetemperature from falling below about 32° C. The control system can beprogrammed to cause the LPEC to cool the temperature of the blood to avalue within the range of about 10° C. to about 30° C.

CONCLUSION

While various inventive embodiments have been described and illustratedherein, those of ordinary skill in the art will readily envision avariety of other means and/or structures for performing the functionand/or obtaining the results and/or one or more of the advantagesdescribed herein, and each of such variations and/or modifications isdeemed to be within the scope of the inventive embodiments describedherein. More generally, those skilled in the art will readily appreciatethat all parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the inventive teachingsis/are used. Those skilled in the art will recognize, or be able toascertain using no more than routine experimentation, many equivalentsto the specific inventive embodiments described herein. It is,therefore, to be understood that the foregoing embodiments are presentedby way of example only and that, within the scope of the appended claimsand equivalents thereto, inventive embodiments may be practicedotherwise than as specifically described and claimed. Inventiveembodiments of the present disclosure are directed to each individualfeature, system, article, material, kit, and/or method described herein.In addition, any combination of two or more such features, systems,articles, materials, kits, and/or methods, if such features, systems,articles, materials, kits, and/or methods are not mutually inconsistent,is included within the inventive scope of the present disclosure.

The above-described embodiments of the invention can be implemented inany of numerous ways. For example, some embodiments may be implementedusing hardware, software or a combination thereof. When any aspect of anembodiment is implemented at least in part in software, the softwarecode can be executed on any suitable processor or collection ofprocessors, whether provided in a single computer or distributed amongmultiple computers.

In this respect, various aspects of the invention may be embodied atleast in part as a computer readable storage medium (or multiplecomputer readable storage media) (e.g., a computer memory, one or morefloppy disks, compact disks, optical disks, magnetic tapes, flashmemories, circuit configurations in Field Programmable Gate Arrays orother semiconductor devices, or other tangible computer storage mediumor non-transitory medium) encoded with one or more programs that, whenexecuted on one or more computers or other processors, perform methodsthat implement the various embodiments of the technology discussedabove. The computer readable medium or media can be transportable, suchthat the program or programs stored thereon can be loaded onto one ormore different computers or other processors to implement variousaspects of the present technology as discussed above.

The terms “program” or “software” are used herein in a generic sense torefer to any type of computer code or set of computer-executableinstructions that can be employed to program a computer or otherprocessor to implement various aspects of the present technology asdiscussed above. Additionally, it should be appreciated that accordingto one aspect of this embodiment, one or more computer programs thatwhen executed perform methods of the present technology need not resideon a single computer or processor, but may be distributed in a modularfashion amongst a number of different computers or processors toimplement various aspects of the present technology.

Computer-executable instructions may be in many forms, such as programmodules, executed by one or more computers or other devices. Generally,program modules include routines, programs, objects, components, datastructures, etc. that perform particular tasks or implement particularabstract data types. Typically the functionality of the program modulesmay be combined or distributed as desired in various embodiments.

Also, the technology described herein may be embodied as a method, ofwhich at least one example has been provided. The acts performed as partof the method may be ordered in any suitable way. Accordingly,embodiments may be constructed in which acts are performed in an orderdifferent than illustrated, which may include performing some actssimultaneously, even though shown as sequential acts in illustrativeembodiments.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is:
 1. A system for providing support comprising: alocal perfusion extracorporeal circuit (LPEC) for perfusing a localtarget region of a body, comprising: a LPEC input flow port; a LPECoutput flow port; the LPEC input flow port and LPEC output flow port forcontacting blood flowing within the vasculature to the local targetregion of the body; a LPEC pump; and a LPEC heat exchanger forcontrolling the temperature of the blood returned to the local targetregion of the body for the local perfusion; a controlled flowpartitioning system disposed proximate to a distal tip of a LPECinjector member, the controlled flow partitioning system comprising: afirst pressure sensor for measuring a first pressure proximate to thedistal tip of the LPEC injector member; and a second pressure sensor formeasuring a second pressure, the second pressure sensor being disposedproximal from the distal tip of the LPEC injector member; wherein thesecond pump serves as an injection flow rate source to cause injectionflow at a predetermined flow rate pattern at the injector member; asystemic perfusion extracorporeal circuit (SPEC) comprising: a SPECinput flow port; a SPEC output flow port; the SPEC input flow port andSPEC output flow port for contacting blood flowing within thevasculature at a peripheral portion of the body; and a SPEC pump; one ormore SPEC temperature sensors for coupling to the body, to indicateaverage core body temperature and/or average system temperature of thebody perfused by the SPEC; one or more LPEC temperature sensors forcoupling to the local target region of the body to indicate temperaturewithin the target region; and a console comprising at least oneprocessing unit programmed to: receive data indicative of measurementsof the first pressure and the second pressure over a time interval Twith the flow of blood injected at the distal tip at the predeterminedflow rate pattern; and compute the conductance as at least one of aproximal exterior conductance and a distal exterior conductance at thedistal tip of the LPEC injector member, using the data indicative of themeasurements of the first pressure and the second pressure and thepredetermined flow rate pattern.
 2. The system of claim 1, wherein thepredetermined flow rate pattern comprises a first constant flow rateover a first time interval t₁<T, and a second constant flow ratedifferent from the first constant flow rate over a second time intervalt₂<T subsequent to the first time interval.
 3. The system of claim 2,wherein the at least one processing unit is further programmed to causethe injection flow rate source to: control the flow of fluid injected atthe distal tip over the first time interval t₁ to the first constantflow rate; and control the flow of fluid injected at the distal tip overthe second time interval t₂ to the second constant flow rate.
 4. Thesystem of claim 3, wherein the at least one processing unit is furtherprogrammed to: record first measurements of the first pressure and thesecond pressure over the first time interval t₁ using the first pressuresensor and the second pressure sensor; and record second measurements ofthe first pressure and the second pressure over the second time intervalt₂ using the first pressure sensor and the second pressure sensor. 5.The system of claim 4, wherein the at least one of the proximal exteriorconductance or the distal exterior conductance at the distal tip iscomputed using data indicative of the first measurements of the firstpressure and the second pressure, the second measurements of the firstpressure and the second pressure, the first constant flow rate, and thesecond constant flow rate.
 6. The system of claim 2, wherein the atleast one processing unit is further programmed to compute a projectionof at least one of the proximal exterior conductance or the distalexterior conductance over a third time interval later than the firsttime interval and the second time interval.
 7. The system of claim 1,wherein the local target region is the brain.
 8. The system of claim 1,wherein the LPEC input flow port is disposed in contact with one of theleft common carotid artery, right common carotid artery, and an arterydownstream of one of those locations.
 9. The system of claim 1, whereinthe systemic perfusion circuit is an emergency extracorporeal membraneoxygenation support.
 10. The system of claim 1, wherein the one or moreSPEC temperature sensors comprise a bladder temperature sensor and/or arectal temperature sensor.
 11. The system of claim 1, further comprisinga control system programmed to execute a control procedure, the controlprocedure comprising: causing the SPEC to adjust the systemictemperature of the body such that the one or more SPEC temperaturesensors indicate an average temperature within the range from about 32°C. to less than about 37° C.; and causing the LPEC to control thetemperature of the blood to the target region such that the one or moreLPEC temperature sensors indicate a temperature below about 30° C.,wherein the control system is programmed to set a flow rate and atemperature at the LPEC pump and LPEC heat exchanger independently froma flow rate at the SPEC pump.
 12. The system of claim 11, wherein thecontrol system is programmed to cause the LPEC to control thetemperature of the blood to the target region automatically, or based ona manual input.
 13. The system of claim 11, wherein the control systemis further programmed to cause the SPEC to increase the temperature ofthe blood to prevent the average temperature from falling below about32° C.
 14. The system of claim 11, wherein the control system isprogrammed to cause the LPEC to cool the temperature of the blood to avalue within the range of about 10° C. to about 30° C.